Malignant Carcinoid Syndrome Treatment & Management

Updated: Aug 03, 2021
  • Author: Luigi Santacroce, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Medical Care

Systemic therapy should be used to control humorally mediated symptoms when the cancer spreads elsewhere. Initially, somatostatin analogs are useful in approximately 40% of patients. [39] Histamine blockers may also be useful. Diarrhea generally responds to standard antidiarrheal medications, but serotonin antagonists should be administered, if necessary, to control diarrhea and malabsorption. Severe and prolonged carcinoid crises associated with bronchial or stomach carcinoids may respond to corticosteroid treatment.

Somatostatin Analogs

The somatostatin analogs octreotide and lanreotide are used to control carcinoid symptoms and tumor progression in advanced inoperable disease. [40, 41] These synthetic somatostatin analogs have high affinity for somatostatin receptors and are preferred to native somatostatin because of a longer half-life (average half-life of somatostatin is 2 min; that of octreotide is 2 h, and that of lanreotide, 23-36 days).

The PROMID Study Group demonstrated the ability of somatostatin analogs to control the growth of well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors (NETs). [42] The phase IIIB study randomized 85 treatment-naive patients with mid-gut NETs to receive either placebo or octreotide long-acting repeatable (LAR) 30 mg IM monthly until tumor progression or death.

Median time to tumor progression (the primary efficacy endpoint) proved significantly longer in treatment with octreotide LAR than with placebo (14.3 vs 6 months, hazard ratio [HR] = 0.34; 95% confidence interval [CI], 0.20-0.59; P = 0.000072). Secondary endpoints included tumor response and survival time. At 6 months of treatment, more patients had stable disease in the octreotide LAR group compared with placebo (66.7% vs 37.2%) with similar responses in functionally active and inactive tumors. Survival analysis was reported as not confirmatory due to the low number of deaths.

Octreotide LAR significantly extends the time to tumor progression compared with placebo for patients with midgut NETs. A randomized, placebo-controlled phase 3 trial found that everolimus plus octreotide LAR improved progression-free survival in patients with advanced NETs associated with carcinoid syndrome. [43]

A retrospective study suggested a possible survival benefit for the use of octreotide LAR in elderly patients with distant-stage NET with carcinoid syndrome. The 5-year survival benefit for was significant for patients with distant-stage disease (HR, 0.61; P ≤ .001) but not for the patients with local/regional stage disease.

In the CLARINET study, lanreotide was associated with significantly prolonged progression-free survival compared with placebo (median not reached vs. median of 18.0 months, P< 0.001). The study included patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor–positive neuroendocrine tumors of grade 1 or 2, who received extended-release aqueous-gel formulation of lanreotide at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. [44]

Over time, long-acting somatostatin analogs may become less effective at controlling carcinoid symptoms. [45] In such cases, European Society for Medical Oncology (ESMO) guidelines recommend reducing the injection interval from every 4 weeks to every 3 weeks, or even every 2 weeks, or adding short‐acting octreotide. [46] Although more-frequent dosing is common in clinical practice, it is an off-label use of these agents. [45] Treatment with pasireotide LAR is another off-label approach. Interferon alpha is approved for NET symptom control but has a less favorable toxicity profile and is usually added as second-line therapy for refractory symptoms. [46]

In 2018, the US Food and Drug Administration (FDA) approved llutetium-177 (177Lu)–dotatate (LUTATHERA), a radiolabeled somatostatin analog, for the treatment of somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (including foregut, midgut, and hindgut neuroendocrine tumors) in adults. [47] Approval was based on data from the NETTER-1 trial, which showed superior progression-free survival (PFS) with 177Lu–Dotatate compared with high-dose long-acting octreotide. [48]  An update of NETTER-1 confirmed the clinically and statistically meaningful PFS benefit of 177Lu-dotatate, suggested an overall survival benefit, and demonstrated a significant quality of life benefit (eg, reduced fatigue, pain, and diarrhea), compared with high-dose octreotide. [49]

Tryptophan hydroxylase inhibitor

Telostristat ethyl (Xermelo) was approved by the FDA in 2017 for carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by a somatostatin analog. Telostristat ethyl is a prodrug that is metabolized to telotristat, which inhibits tryptophan hydroxylase, the rate-limiting step in serotonin biosynthesis.

The safety and efficacy of telotristat were established in a 12-week, double-blind, placebo-controlled trial in 135 patients who were experiencing 4 or more bowel movements per day despite the use of a somatostatin analog and were randomly assigned to add placebo or telotristat three times daily. Reduction in bowel movement frequency of ≥30% from baseline for ≥50% of the double-blind treatment period was observed in 44% of patients given telotristat ethyl 250 mg, 42% of those given telotristat ethyl 500 mg, and 20% of those receiving placebo. The FDA approved the 250 mg TID dosage regimen. [50]  

A long-term safety study found that telotristat ethyl is well tolerated and has a favorable safety profile in patients with carcinoid syndrome. Mean duration of exposure and follow-up was 1.3 years (range,1 week to 5.7 years), with 309 total patient-years of exposure. No deaths were attributable to telotristat ethyl. [51]

Other approaches

Patients benefit from specific drugs that either suppress production of vasoactive amines or block the peripheral effects. These agents include alpha-adrenergic blocking drugs, cyproheptadine, and H2-receptor blockers.

Interferon-alpha may help control carcinoid symptoms or arrest tumor growth and reportedly may be effective in patients in whom octreotide treatment has failed; however, benefits are generally transient and accompanied by adverse effects. The combination of interferon-alpha and continuous infusion of 5-fluorouracil (5-FU) has demonstrated antitumoral and antihormonal activity and can provide symptom palliation. [52]

Radiotherapy or chemotherapy with streptozotocin, cisplatin, etoposide, and doxorubicin, either alone or in combination, has been used, and reports show some success; a good response occurs in only 20-30% of cases. The role of radiation therapy in the management of carcinoid tumors with distant metastasis is restricted to symptomatic palliation of the painful bone metastases. This therapy is not useful for treating liver metastases or for other nonskeletal tissues. However, Jia and Wang reported that radioembolization with yttrium-90 (90Y) microspheres can improve the survival rate and tumor response in patients with unresectable liver metastases. [53]

Therapy with metaiodobenzylguanidine (MIBG) has  been studied. In a review that included 20 patients with advanced metastatic carcinoid tumors, Ezziddin et al reported that treatment with 131iodine-MIBG provided safe and effective palliation of symptoms and stabilization of disease. [54]  

Little evidence suggests that chemotherapy, either traditional or by continuous infusion, helps improve patient survival rates. Failure to respond to one chemotherapy combination does not necessarily mean another combination will also be ineffectual.


Surgical Care

Complete surgical removal of all tumor tissues, when feasible, is the best treatment because it may result in a complete and permanent cure. The aim of surgical therapy is to reduce the tumor mass and obtain symptom remission. Performing a curative resection, mass debulking, or hepatic embolization is possible.

Cytoreductive surgery has been reported to have the best impact on symptom regression and overall survival. [55] An extensive surgical excision, including the adjacent mesentery, must be performed.

Surgical considerations include the following:

  • Surgery should always be considered in patients with large or extensive hepatic metastases involving surgically accessible areas of the liver.

  • For lesions in the distal ileum, a right hemicolectomy is necessary to remove the lymphatic drainage adequately.

  • For tumors located in the appendix that are smaller than 1.5 cm in diameter, appendectomy is suitable and curative in 100% of patients. The involvement of the mesoappendix does not alter the patient's prognosis, but invasion of the cecum mandates more radical surgery (eg, right hemicolectomy with regional lymphadenectomy). Carcinoids in children usually occur in the appendix, and the appendectomy results in a complete cure.

  • Rectal carcinoids, if smaller than 1.5 cm in diameter, should be treated with local excision; if rectal carcinoids are larger than 1.5 cm, they must be considered malignant, and abdominoperineal resection (Miles operation) or low anterior resection should be performed.

Hepatic transplantation has also been attempted in selected patients, with promising results; however, generalization for this treatment option, because it is extremely expensive and debilitating, is not possible without more long-term studies.

Surgery should also be considered for resection of hepatic recurrence, even after previous resection, but only if the lesions are in an area where resection can be performed with minimal morbidity.

  • The whole intestine should be examined at the time of surgery to detect eventual multiple lesions. [56]

  • Chemoembolization with hepatic artery infusion of 5-FU or doxorubicin, combined with embolization of the hepatic artery with collagen fibers, causes substantial tumor necrosis. This procedure reportedly decreases tumor bulk of liver metastases from carcinoid tumors by more than 50% in as many as 60% of patients. [57]

  • Adverse effects of embolization are frequent and may be severe (see Tumor Lysis Syndrome).

  • Other surgical techniques, ablative but nonresective, include cryosurgery and percutaneous alcohol injections.

For any patient with controlled carcinoid symptoms and heart involvement, cardiac surgery must be considered for symptomatic carcinoid heart disease and must be performed by an experienced team (including medical, surgical, and anesthesiology experts) in order to provide the best management of this condition. [58, 59] For patients with silent disease and symptomatic carcinoid heart disease, valve replacement should be considered. [60]

Surgical resection can provide effective palliation in carefully selected patients. Debulking hepatic metastases may palliate systemic symptoms, and intestinal resection is highly effective in relieving symptoms of intestinal obstruction and ischemia. [61]

For pulmonary carcinoids, surgical resection remains the gold standard. However, minimally invasive endobronchial procedures have emerged as a parenchyma-sparing alternative for tumors located in the central airways. [62]

Palliative surgery may be associated with substantial morbidity, and the effects are often transient. However, a retrospective nonrandomized study suggests that patients with carcinoid heart disease who undergo hepatic resection have decreased cardiac progression and improved prognosis. [63]



Consult with either a cardiologist or pneumologist for cardiac and respiratory assessment. A systematic psychotherapeutic intervention may be very helpful in patients with carcinoid.



In patients with malignant carcinoid syndrome, diarrhea and weight loss are severe problems that need to be controlled.

  • The major nutrients are absorbed easily and do not exacerbate the diarrhea, while most vegetables are very irritating.

  • Patients with severe diarrhea should be careful to avoid dehydration or vitamin deficiency. Nicotinamide and niacin supplements are very useful and must be prescribed, along with potassium, magnesium, iron, and essential elements.

  • Always recommend increased protein in the diet.



Mild (not stressful) physical activity is not harmful and is possible if desired. No intense physical activities are allowed.